The ATP receptors are roughly classified into the P2X family of the ion channel type receptors, and the P2Y family of the G protein coupling type receptors, and seven kinds (P2X1 to P2X7) and eight kinds (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 to P2Y14) of subtypes have so far been reported for each family.
The P2X4 receptor (Genebank No. X87763), a subtype of the P2X family, has been reported to be widely expressed in the central nervous system, and the like (Non-patent documents 1 to 5).
The onset mechanisms of chronic or intractable pains including neuropathic pain have not been fully elucidated, and if non-steroidal anti-inflammatory drugs (NSAIDs) and morphine are not effective for such a pain, no therapy is available for that pain. Therefore, very heavy physical and mental burdens are given to patients and people around them. Neuropathic pain is often caused by injury of a peripheral nerve or the central nerve, and it is caused by, for example, after-trouble of operation, cancer, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia, and the like.
Recently, Inoue et al. verified the involvement of the P2X receptor in neuropathic pain by using a spinal nerve-damaged animal model in which allodynia can be detected, and they described that nerve-damaged type unusual pain (especially allodynia) is induced through the P2X4 receptor expressed in the microglia cells of the spinal cord (Non-patent documents 6 and 7, and Patent document 1).
Therefore, a substance that inhibits the activity of the P2X4 receptor is expected to be a prophylactic or therapeutic agent for pains of nociceptive pain, inflammatory pain, and neuropathic pain caused by after-trouble of operation, cancers, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia, and the like.
Patent document 2 reported that a benzofuro-1,4-diazepin-2-one derivative represented by the following general formula (A):
(in the formula, R1 is a halogen, and R2 is hydrogen, a halogen, nitro, cyano, C(O)—OR3, C(O)—NR4R5, SO2—OR3, or SO2—NR4R5, or R1 is hydrogen, and R2 is a halogen, nitro, cyano, C(O)—OR3, C(O)—NR4R5, SO2—OR3, or SO2—NR4R5) has a P2X4 receptor antagonist activity.
It was also reported that paroxetine, which is an antidepressant, has a P2X4 receptor antagonist activity (Non-patent document 8).
The inventors of the present invention also found that a naphtho[1,2-e][1,4]diazepin-2-one derivative represented by the following formula (B):
(in the formula, RI represents hydrogen, a lower alkyl, a lower alkoxy, and the like, and RII represents hydroxy, a lower alkyl, a lower alkoxy, tetrazolyl group, and the like).
a naphtho[1,2-b][1,4]diazepin-2,4-dione derivative represented by the Mowing general formula (C):
(in the formula, RIII represents hydrogen, a lower alkyl, a lower alkoxy, and the like, and RIV represents hydrogen, a lower alkyl, a lower alkoxy, tetrazolyl group, and the like), and related compounds thereof have a P2X4 receptor antagonist activity, and filed patent applications therefor (Patent documents 3 to 10).